We are using mice with genetic defects in craniofacial development or differences in susceptibility to teratogens as models to study the mechanisms involved in craniofacial malformation. Mutations that cause cleft lip, cleft palate, malocclusion and exencephaly have been found to have chondrocytes that produce altered cartilage matrix. Several different genetic defects in matrix biochemistry result in similar malformation syndromes. Other mutant genes reduce or render defective essential cellular processes such as keratinization or other types of cell differentiation with resultant malformation. Other genes that modify the action of teratogenic drugs are used to explore the mechanisms of teratogenesis and to develop sensitive test systems for recognition of teratogens. These mouse genetic test systems are produced using uniform, highly inbred, genetically defined strains and timed mating resulting in control of stages of development for tests of target tissues at critical periods of susceptibility in vivo or in vitro. Organs or organ primordia such as limb buds or cells from embryos of appropriate genetic type and developmental stage are labeled in vivo or in vitro with isotopic precursors for specific structural molecules in order to determine the mechanisms of gene action in development and the mechanisms of teratogenesis. These methods have proven successful in identification molecular defects in cartilage matrix and other specific molecular errors that result in malformation. We are continuing to use this approach to determine the molecular vocabulary of development.